| 1. |
- Jönsson, Göran B, et al.
(författare)
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High-resolution genomic profiles of breast cancer cell lines assessed by tiling BAC array comparative genomic hybridization.
- 2007
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 46:6, s. 543-558
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Tidskriftsartikel (refereegranskat)abstract
- A BAC-array platform for comparative genomic hybridization was constructed from a library of 32,433 clones providing complete genome coverage, and evaluated by screening for DNA copy number changes in 10 breast cancer cell lines (BT474, MCF7, HCC1937, SK-BR-3, L56Br-C1, ZR-75-1, JIMTI, MDA-MB-231, MDA-MB-361, and HCC2218) and one cell line derived from fibrocystic disease of the breast (MCF10A). These were also characterized by gene expression analysis and found to represent all five recently described breast cancer subtypes using the '' intrinsic gene set '' and centroid correlation. Three cell lines, HCC 1937 and L56BrC1 derived from BRCA I mutation carriers and MDA-MB-23 1, were of basal-like subtype and characterized by a high frequency of low-level gains and losses of typical pattern, including limited deletions on Sq. Four estrogen receptor positive cell lines were of luminal A subtype and characterized by a different pattern of aberrations and high-level amplifications, including ERBB2 and other 17q amplicons in BT474 and MDA-MB-361. SK-BR-3 cells, characterized by a complex genome including ERBB2 amplification, massive high-level amplifications on 8q and a homozygous deletion of CDH1 at 16q22, had an expression signature closest to luminal B subtype. The effects of gene amplifications were verified by gene expression analysis to distinguish targeted genes from silent amplicon passengers. JIMT1, derived from an ERBB2 amplified trastuzumab resistant tumor, was of the ERBB2 subtype. Homozygous deletions included other known targets such as PTEN (HCC1937) and CDKN2A (MDA-MB-231, MCF10A), but also new candidate suppressor genes such as FUSSEL18 (HCC1937) and WDR11 (L56Br-C1) as well as regions without known genes. The tiling BAC-arrays constitute a powerful tool for high-resolution genomic profiling suitable for cancer research and clinical diagnostics.
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| 2. |
- Borg, Markus, et al.
(författare)
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Time extraction from real-time generated football reports
- 2007
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Ingår i: [Host publication title missing]. - 9789985405130 ; , s. 37-43
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Konferensbidrag (refereegranskat)abstract
- This paper describes a system to extract events and time information from football match reports generated through minute-by-minute reporting. We describe a method that uses regular expressions to find the events and divides them into different types to determine in which order they occurred. In addition, our system detects time expressions and we present a way to structure the collected data using XML.
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| 3. |
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| 4. |
- Davidsson, Josef, et al.
(författare)
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Tiling resolution array comparative genomic hybridization, expression and methylation analyses of dup(1q) in Burkitt lymphomas and pediatric high hyperdiploid acute lymphoblastic leukemias reveal clustered near-centromeric breakpoints and overexpression of genes in 1q22-32.3
- 2007
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 16:18, s. 2215-2225
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Tidskriftsartikel (refereegranskat)abstract
- Although gain of 1q occurs in 25% of Burkitt lymphomas (BLs) and 10% of pediatric high hyperdiploid acute lymphoblastic leukemias (ALLs), little is known about the origin, molecular genetic characteristics and functional outcome of dup(1q) in these disorders. Ten dup(1q)-positive BLs/ALLs were investigated by tiling resolution (32k) array CGH analysis, which revealed that the proximal breakpoints in all cases were near-centromeric, in eight of them clustering within a 1.4 Mb segment in 1q12-21.1. The 1q distal breakpoints were heterogeneous, being more distal in the ALLs than in the BLs. The minimally gained segments in the ALLs and BLs were 57.4 Mb [dup(1)(q22q32.3)] and 35 Mb [dup(1)(q12q25.2)], respectively. Satellite 11 DNA on 1q was not hypomethylated, as ascertained by Southern blot analyses of 15 BLs/ALLs with and without gain of 1q, indicating that aberrant methylation was not involved in the origin of dup(1q), as previously suggested for other neoplasms with 1q rearrangements. Global gene expression analyses revealed that five genes in the minimally 57.4 Mb gained region-B4GALT3, DAP3, RGS16, TMEM183A and UCK2-were significantly overexpressed in dup(1q)-positive ALLs compared with high hyperdiploid ALLs without dup(1q). The DAP3 and UCK2 genes were among the most overexpressed genes in the BL case with gain of 1q investigated. The DAP3 protein has been reported to be highly expressed in invasive glioblastoma multiforme cells, whereas expression of the UCK2 protein has been correlated with sensitivity to anticancer drugs. However, involvement of these genes in dup(1q)-positive ALLs and BLs has previously not been reported.
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| 5. |
- Ferreira da Silva, Eduardo, et al.
(författare)
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Heavy metal pollution downstream the abandoned Coval da Mó mine (Portugal) and associated effects on epilithic diatom communities
- 2009
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Ingår i: Science of the Total Environment. - : Elsevier BV. - 0048-9697 .- 1879-1026. ; 407:21, s. 5620-5636
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Tidskriftsartikel (refereegranskat)abstract
- This study examined trace-element concentrations in 39 sediment samples collected in the vicinity of the abandoned Coval da Mó mine, and evaluated the anthropogenic contaminant effects and other environmental variables in the taxonomic composition, structure and morphological changes of benthic diatom communities.The results show the existence of extremely high contamination in Pb, Zn and Cd (the mean values exceed the background values 376, 96 and 19 times, respectively) on the first 2.5 km in the water flow direction. Also Co, Cu, Mn and Ni are present in high concentrations. Dilution by relatively uncontaminated sediment reduces metal concentrations downstream, but Zn concentrations increase downstream Fílvida stream, as a result of several factors such as sewage and agriculture.To evaluate the biological effects caused by Pb, Cd and Zn, three sites were selected. In the stressed environment, near the mining area (C232), diatoms were extremely rare, however there was a slight recovery at site C79 located 2 km downstream. Fragilaria capucina var. rumpens, Fragilaria cf. crotonensis and Achnanthidium minutissimum showed abnormal valves which may be related to high levels of metals.Six km downstream, in Fílvida stream (C85), an increase in species richness and diversity was registered while the relative percentage of valve teratologies was lower. In the absence of OM, nutrients and low pH the diatom community patterns must be attributed to the metal concentration at some sites. Considering that community diversity can be affected by abiotic and biotic variables and valve deformations are caused by a small number of variables, basically metals, and acid conditions, we consider the presence of teratologies as an indication of the presence of metals.
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| 6. |
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| 7. |
- Heidenblad, Markus, et al.
(författare)
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Tiling resolution array CGH and high density expression profiling of urothelial carcinomas delineate genomic amplicons and candidate target genes specific for advanced tumors.
- 2008
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Ingår i: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 1:Jan 31
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: Urothelial carcinoma (UC) is characterized by nonrandom chromosomal aberrations, varying from one or a few changes in early-stage and low-grade tumors, to highly rearranged karyotypes in muscle-invasive lesions. Recent array-CGH analyses have shed further light on the genomic changes underlying the neoplastic development of UC, and have facilitated the molecular delineation amplified and deleted regions to the level of specific candidate genes. In the present investigation we combine detailed genomic information with expression information to identify putative target genes for genomic amplifications. METHODS: We analyzed 38 urothelial carcinomas by whole-genome tiling resolution array-CGH and high density expression profiling to identify putative target genes in common genomic amplifications. When necessary expression profiling was complemented with Q-PCR of individual genes. RESULTS: Three genomic segments were frequently and exclusively amplified in high grade tumors; 1q23, 6p22 and 8q22, respectively. Detailed mapping of the 1q23 segment showed a heterogeneous amplification pattern and no obvious commonly amplified region. The 6p22 amplicon was defined by a 1.8 Mb core region present in all amplifications, flanked both distally and proximally by segments amplified to a lesser extent. By combining genomic profiles with expression profiles we could show that amplification of E2F3, CDKAL1, SOX4, and MBOAT1 as well as NUP153, AOF1, FAM8A1 and DEK in 6p22 was associated with increased gene expression. Amplification of the 8q22 segment was primarily associated with YWHAZ (14-3-3-zeta) and POLR2K over expression. The possible importance of the YWHA genes in the development of urothelial carcinomas was supported by another recurrent amplicon paralogous to 8q22, in 2p25, where increased copy numbers lead to enhanced expression of YWHAQ (14-3-3-theta). Homozygous deletions were identified at 10 different genomic locations, most frequently affecting CDKN2A/CDKN2B in 9p21 (32%). Notably, the latter occurred mutually exclusive with 6p22 amplifications. CONCLUSION: The presented data indicates 6p22 as a composite amplicon with more than one possible target gene. The data also suggests that amplification of 6p22 and homozygous deletions of 9p21 may have complementary roles. Furthermore, the analysis of paralogous regions that showed genomic amplification indicated altered expression of YWHA (14-3-3) genes as important events in the development of UC.
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| 8. |
- Honeth, Gabriella, et al.
(författare)
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The CD44(+)/CD24(-) phenotype is enriched in basal-like breast tumors
- 2008
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 10:3
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Human breast tumors are heterogeneous and consist of phenotypically diverse cells. Breast cancer cells with a CD44(+)/CD24(-) phenotype have been suggested to have tumor-initiating properties with stem cell-like and invasive features, although it is unclear whether their presence within a tumor has clinical implications. There is also a large heterogeneity between tumors, illustrated by reproducible stratification into various subtypes based on gene expression profiles or histopathological features. We have explored the prevalence of cells with different CD44/CD24 phenotypes within breast cancer subtypes. Methods Double-staining immunohistochemistry was used to quantify CD44 and CD24 expression in 240 human breast tumors for which information on other tumor markers and clinical characteristics was available. Gene expression data were also accessible for a cohort of the material. Results A considerable heterogeneity in CD44 and CD24 expression was seen both between and within tumors. A complete lack of both proteins was evident in 35% of the tumors, while 13% contained cells of more than one of the CD44(+)/CD24(-), CD44(-)/CD24(+) and CD44(+)/CD24(+) phenotypes. CD44(+)/CD24(-) cells were detected in 31% of the tumors, ranging in proportion from only a few to close to 100% of tumor cells. The CD44(+)/CD24(-) phenotype was most common in the basal-like subgroup-characterized as negative for the estrogen and progesterone receptors as well as for HER2, and as positive for cytokeratin 5/14 and/or epidermal growth factor receptor, and particularly common in BRCA1 hereditary tumors, of which 94% contained CD44(+)/CD24(-) cells. The CD44(+)/CD24(-) phenotype was surprisingly scarce in HER2+ tumors, which had a predominantly CD24(+) status. A CD44(+)/CD24(-) gene expression signature was generated, which included CD44 and alpha(6)-integrin (CD49f) among the top-ranked overexpressed genes. Conclusion We demonstrate an association between basal-like and particularly BRCA1 hereditary breast cancer and the presence of CD44(+)/CD24(-) cells. Not all basal-like tumors and very few HER2+ tumors, however, contain CD44(+)/CD24(-) cells, emphasizing that a putative tumorigenic ability may not be confined to cells of this phenotype and that other breast cancer stem cell markers remain to be identified.
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| 9. |
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| 10. |
- Jönsson, Göran B, et al.
(författare)
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Genomic profiling of malignant melanoma using tiling-resolution arrayCGH.
- 2007
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 26:32, s. 4738-4748
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Tidskriftsartikel (refereegranskat)abstract
- Malignant melanoma is an aggressive, heterogeneous disease where new biomarkers for diagnosis and clinical outcome are needed. We searched for chromosomal aberrations that characterize its pathogenesis using 47 different melanoma cell lines and tiling-resolution bacterial artificial chromosome-arrays for comparative genomic hybridization. Major melanoma genes, including BRAF, NRAS, CDKN2A, TP53, CTNNB1, CDK4 and PTEN, were examined for mutations. Distinct copy number alterations were detected, including loss or gain of whole chromosomes but also minute amplifications and homozygous deletions. Most common overlapping regions with losses were mapped to 9p24.3–q13, 10 and 11q14.1-qter, whereas copy number gains were most frequent on chromosomes 1q, 7, 17q and 20q. Amplifications were delineated to oncogenes such as MITF (3p14), CCND1 (11q13), MDM2 (12q15), CCNE1 (19q12) and NOTCH2 (1p12). Frequent findings of homozygous deletions on 9p21 and 10q23 confirmed the importance of CDKN2A and PTEN. Pair-wise comparisons revealed distinct sets of alterations, for example, mutually exclusive mutations in BRAF and NRAS, mutual mutations in BRAF and PTEN, concomitant chromosome 7 gain and 10 loss and concomitant chromosome 15q22.2–q26.3 gain and 20 gain. Moreover, alterations of the various melanoma genes were associated with distinct chromosomal imbalances suggestive of specific genomic programs in melanoma development.
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| 11. |
- Lundin, Catarina, et al.
(författare)
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Tiling resolution array CGH of dic(7;9)(p11 approximately 13;p11 approximately 13) in B-cell precursor acute lymphoblastic leukemia reveals clustered breakpoints at 7p11.2 approximately 12.1 and 9p13.1.
- 2007
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Ingår i: Cytogenetic and Genome Research. - : S. Karger AG. - 1424-859X .- 1424-8581. ; 118:1, s. 13-18
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Tidskriftsartikel (refereegranskat)abstract
- The dic( 7; 9)( p11 similar to 13; p11 similar to 13) is a recurrent chromosomal abnormality in acute lymphoblastic leukemia (ALL), mainly of B-lineage. Although more than 20 dic(7; 9)-positive ALLs have been reported to date, the molecular genetic consequences of this aberration are unknown. We performed tiling resolution (32K) genome-wide array-based comparative genomic hybridization ( array CGH) analysis of three cases with dic(7; 9) in order to characterize the breakpoints on 7p and 9p. The analysis showed a clustering of breakpoints within 9p13.1 in all three cases and within 7p11.2 in two cases; the array CGH revealed two different breakpoints - 7p12.1 and 7p14.1 - in the remaining case. Based on these findings the abnormality should hence be designated dic(7; 9)(p11.2 similar to 12.1; p13.1). Locus-specific fluorescence in situ hybridization analysis of one of the cases narrowed down the 7p11.2 breakpoint to a < 500-kb segment in this sub-band, a region containing three known genes. Unfortunately, lack of material precluded further molecular genetic studies, and it thus remains unknown whether the pathogenetically important outcome of the dic(7; 9) is formation of a chimeric gene or loss of 7p and/or 9p material. Copyright (c) 2007 S. Karger AG, Basel.
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| 12. |
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| 13. |
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| 14. |
- Saal, Lao, et al.
(författare)
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Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity
- 2007
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 104:18, s. 7564-7569
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Tidskriftsartikel (refereegranskat)abstract
- Pathway-specific therapy is the future of cancer management. The oncogenic phosphatidylinositol 3-kinase (P13K) pathway is frequently activated in solid tumors; however, currently, no reliable test for P13K pathway activation exists for human tumors. Taking advantage of the observation that loss of PTEN, the negative regulator of P13K, results in robust activation of this pathway, we developed and validated a microarray gene expression signature for immunohistochemistry (IHC)-detectable PTEN loss in breast cancer (IBC). The most significant signature gene was PTEN itself, indicating that PTEN mRNA levels are the primary determinant of PTEN protein levels in BC. Some PTEN IHC-positive BCs exhibited the signature of PTEN loss, which was associated to moderately reduced PTEN mRNA levels cooperating with specific types of PIK3CA mutations and/or amplification of HER2. This demonstrates that the signature is more sensitive than PTEN IHC for identifying tumors with pathway activation. In independent data sets of breast, prostate, and bladder carcinoma, prediction of pathway activity by the signature correlated significantly to poor patient outcome. Stathmin, encoded by the signature gene STMN1, was an accurate IHC marker of the signature and had prognostic significance in BC. Stathmin was also pathway-pharmacodynamic in vitro and in vivo. Thus, the signature or its components such as stathmin may be clinically useful tests for stratification of patients for anti-P13K pathway therapy and monitoring therapeutic efficacy. This study indicates that aberrant P13K pathway signaling is strongly associated with metastasis and poor survival across carcinoma types, highlighting the enormous potential impact on patient survival that pathway inhibition could achieve.
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| 15. |
- Staaf, Johan, et al.
(författare)
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Normalization of Illumina Infinium whole-genome SNP data improves copy number estimates and allelic intensity ratios
- 2008
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Ingår i: BMC Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 9, s. 409-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Illumina Infinium whole genome genotyping (WGG) arrays are increasingly being applied in cancer genomics to study gene copy number alterations and allele-specific aberrations such as loss-of-heterozygosity (LOH). Methods developed for normalization of WGG arrays have mostly focused on diploid, normal samples. However, for cancer samples genomic aberrations may confound normalization and data interpretation. Therefore, we examined the effects of the conventionally used normalization method for Illumina Infinium arrays when applied to cancer samples. RESULTS: We demonstrate an asymmetry in the detection of the two alleles for each SNP, which deleteriously influences both allelic proportions and copy number estimates. The asymmetry is caused by a remaining bias between the two dyes used in the Infinium II assay after using the normalization method in Illumina's proprietary software (BeadStudio). We propose a quantile normalization strategy for correction of this dye bias. We tested the normalization strategy using 535 individual hybridizations from 10 data sets from the analysis of cancer genomes and normal blood samples generated on Illumina Infinium II 300 k version 1 and 2, 370 k and 550 k BeadChips. We show that the proposed normalization strategy successfully removes asymmetry in estimates of both allelic proportions and copy numbers. Additionally, the normalization strategy reduces the technical variation for copy number estimates while retaining the response to copy number alterations. CONCLUSION: The proposed normalization strategy represents a valuable tool that improves the quality of data obtained from Illumina Infinium arrays, in particular when used for LOH and copy number variation studies.
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| 16. |
- Staaf, Johan, et al.
(författare)
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Segmentation-based detection of allelic imbalance and loss-of-heterozygosity in cancer cells using whole genome SNP arrays
- 2008
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1474-7596 .- 1465-6906 .- 1465-6914. ; 9:9
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Tidskriftsartikel (refereegranskat)abstract
- We present a strategy for detection of loss-of-heterozygosity and allelic imbalance in cancer cells from whole genome single nucleotide polymorphism genotyping data. Using a dilution series of a tumor cell line mixed with its paired normal cell line and data generated on Affymetrix and Illumina platforms, including paired tumor-normal samples and tumors characterized by fluorescent in situ hybridization, we demonstrate a high sensitivity and specificity of the strategy for detecting both minute and gross allelic imbalances in heterogeneous tumor samples.
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